Improving the delivery of drugs and other agents to target cells and tissues has been the focus of considerable research for many years. Though many attempts have been made to develop effective methods for importing biologically active molecules into cells, both in vivo and in vitro, none has proved to be entirely satisfactory. Optimizing the association of the inhibitory drug with its intracellular target, while minimizing intercellular redistribution of the drug, e.g., to neighboring cells, is often difficult or inefficient.
Most agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., glucocorticoids and other anti-inflammatory drugs) that can be administered. By comparison, although oral administration of drugs is generally recognized as a convenient and economical method of administration, oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g., blood/brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract. Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues. Benefits of such treatment includes avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells.
Statins lower plasma cholesterol level by decreasing hepatic cholesterol biosynthesis and by upregulating low-density lipoprotein (LDL) receptors on hepatocytes. Their side effects, such as gastrointestinal discomfort, headache, rash and elevations in serum transaminase activity (a sign of hepatotoxicity) have been the principal problems preventing their usage.
Pitavastatin (U.S. Pat. No. 5,856,336), Rosuvastatin (Crestor) (U.S. Pat. No. RE37,314 and U.S. Pat. No. 5,260,440), Pravastatin (U.S. Pat. No. 4,346,227), Fluvastatin (U.S. Pat. Nos. 5,354,772 and 4,739,073), Lovastatin and Sivastatin (mevalonate analogs; U.S. Pat. Nos. 4,231,938and 4,444,784), Cerivastatin (a substituted pyridine; U.S. Pat. No. 5,006,530) are members of the statin class of HMG-CoA reductase inhibitors used as oral treatments for hypercholesterolemia and dyslipidemia. They are structural analogs of the half-reduced intermediate of HMG-CoA and, as such, inhibit the formation of mevalonate.
Compounds such as Pitavastatin and its opened chain form are useful for inhibiting chloesterol biosynthesis and lowering blood cholesterol levels and, as such, are useful in the treatment of atherosclerosis hypercholesterolemia and hyper lipoproteinemia as described in U.S. Pat. No. 5,856,336.
Certain triaryl ethylenes are useful in the treatment of hypercholesterolemia and osteoporosis by acting as selective estrogen receptor modulators. One such derivative, Ospemifene, is described in WO01/36360.
Certain 2,6-dialkylated phenols and their derivatives are useful in the treatment of atherosclerosis and hyperlipedemia through the reduction in the expression of VCAM-1. One such derivative, AGI-1067, is described in U.S. Pat. No. 6,147,250.
Certain trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones and the corresponding ring-opened acids derived therefrom are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful hypolipidemic or hypocholesterolemic agents (U.S. Pat. No. 4,681,893). Atorvastatin, a member of the statin class of HMG-CoA reductase inhibitors, is used as an oral treatment for hypercholesterolemia and dyslipidemia. It is a structural analog of the half-reduced intermediate of HMG-CoA and, as such, inhibits the formation of mevalonate.
Compound ML-236B (U.S. Pat. No. 3,983,140) has been isolated and purified from the metabolic products of microorganisms of the genus Penicillium, especially Penicillium citrinum. It has been shown to inhibit the biosynthesis of cholesterol by enzymes or cultured cells separated from experimental animals by competing with the rate-limiting enzyme active in the biosynthesis of cholesterol, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase and, as a result, significantly reduces serum cholesterol levels of animals (Journal of Antibiotics, 29:1346 (1976)). A number of compounds structurally related to ML-236B also inhibit the biosynthesis of cholesterol. A series of new compounds, which may be prepared by the enzymatic hydroxylation of ML-236B or of derivatives thereof, possess an ability to inhibit the biosynthesis of cholesterol which is at least comparable with, and in some instances substantially exceeds, that of ML-236B itself, are described in U.S. Pat. No. 4,346,227.
Humans as well as other animal organisms need insulin, a pancreatic hormone, in order to utilize glucose. Insulin stimulates the movement of the glucose from the blood into tissue cells, especially muscular cells, and expedites the synthesis of fats as well as of proteins in practically all organs. In diabetics, the pancreas does not produce this hormone in sufficient quantity, resulting in glucose levels in the blood elevating, which causes the known symptoms of diabetes mellitus.
Specific sulfonylureas, which may be administered orally, possess a blood sugar reducing effect, especially in those cases were diabetes occurs during old age (see U.S. Pat. No. 4,146,613). Compounds such as Troglitazone and Rosiglitazone can be useful for blood-glucose lowering activity and are therefore of potential use in the treatment and/or prophylaxis of hyperglycaemia and are of particular use in the treatment of Type II diabetes. These compounds are also useful for the treatment and/or prophylaxis of other diseases including hyperlipidaemia, hypertension, and cardiovascular disease, especially atherosclerosis. In addition these compounds are considered to be useful for treating certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia. (U.S. Pat. No. 6,288,095)
MK-767 (U.S. Pat. No. 6,030,990) is a useful therapeutic agent for the treatment of type-II diabetes. Type-II diabetes is a metabolic disorder characterized by hyperglycemia as well as insulin resistance and/or impaired insulin secretion. MK-767 is a peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist. There are three isoforms of PPARs, α, β, and γ. Although they have similar insulin-like effects, these isoforms act via different mechanisms in different target tissues (Calkin, A. C. et al., Current Opinions in Investigational Drugs, 2003, 4, 4, 444). Experimental data have suggested that drugs combining both PPARα and PPARγ activation may exert a more potent hypotriglyceridemic effect than either compound alone.
Rosiglitazone (U.S. Pat. No. 5,002,953) is a useful therapeutic agent for the treatment of Type II diabetes. Rosiglitazone maleate is an oral antidiabetic agent, which acts primarily by increasing insulin sensitivity. Rosiglitazone improves glycemic control while reducing circulating insulin levels. A number of side effects are associated with rosiglitazone.
Pioglitazone (U.S. Pat. Nos. 5,356,913 and 4,687,777) is a useful therapeutic agent for the treatment of Type II diabetes. Mechanistically, pioglitazone hydrochloride decreases insulin resistance in the periphery and in the liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone hydrochloride, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin.
R-483 (WO 02/080913) is a useful therapeutic agent for the treatment of Type II diabetes. R-483 is a potent agonist for the peroxisome proliferator-activated receptor-gamma (PPAR-γ).
Tesaglitazar (WO 0140171 and U.S. Pat. No. 6,531,622) is a useful therapeutic agent for the treatment of Type II diabetes. Tesaglitazar is a potent agonist for the peroxisome proliferator-activated receptor-gamma and alpha (PPAR-γ and PPAR-α). Activation of PPAR-γ nuclear hormone receptors improves insulin sensitivity. PPAR-α activation decreases serum triglycerides and increases serum HDL-cholestrol. Hypertriglyceridemia and low serum HDL-cholestrol are characteristic of both diabeticdyslipidemia and insulin resistance syndrome. A potent activator of both PPAR-α and PPAR-γ therefore, could possibly replace two classes of drugs used commonly for Type II diabetes, namely selective PPAR-γ activator such as rosiglitazone and pioglitazone and PPAR-α-activating compounds of the fibrate group, such as bezafibrate and fenofibrate.
Thus, there is a need for therapeutic agents for treating metabolic disorders having improved pharmacological properties, e.g., drugs having improved activity for treating hypercholesterolemia, dyslipidemia, hyperlipoproteinemia, osteoporosis, atherosclerosis, hyperlipedemia, hypolipidemic, hypocholesterolemic, hyperglycaemia, type II diabetes, hypertension, cardiovascular disease, atherosclerosis, eating disorders, anorexia nervosa, obesity and/or anorexia bulimia, and pharmacokinetic properties, including improved oral bioavailability, greater potency and extended effective half-life in vivo. New compounds should have fewer side effects, less complicated dosing schedules, and be orally active. In particular, there is a need for a less onerous dosage regimen, such as one pill, once per day.
Assay methods capable of determining the presence or absence of metabolic disease are of practical utility in the search for treatment as well as for diagnosing the presence of metabolic diseases.